Platelet ADP receptor inhibitors

ABSTRACT

Novel compounds of formula (I) to (VI), which more particularly include sulfonylurea derivatives, sulfonylthiourea derivatives, sulfonylguanidine derivatives, sulfonylcyanoguanidine derivatives, thioacylsulfonamide derivatives, and acylsulfonamide derivatives which are effective platelet ADP receptor inhibitors. These derivatives may be used in various pharmaceutical compositions, and are particularly effective for the prevention and/or treatment of cardiovascular diseases, particularly those diseases related to thrombosis. The invention also relates to a method for preventing or treating thrombosis in a mammal comprising the step of administering a therapeutically effective amount of a compound of formulae (I)-(VI), or a pharmaceutically acceptable salt thereof.

FIELD OF THE INVENTION

[0001] The invention relates to novel compounds of formula (I), formula(II), formula (III), formula (IV), formula (V) and formula (VI)(hereinafter referred to as “formulae (I)-(VI)”), which moreparticularly include sulfonylurea derivatives, sulfonylthioureaderivatives, sulfonylguanidine derivatives, sulfonylcyanoguanidinederivatives, thioacylsulfonamide derivatives, and acylsulfonamidederivatives which are effective platelet ADP receptor inhibitors. Thesederivatives may be used in various pharmaceutical compositions, and areparticularly effective for the prevention and/or treatment ofcardiovascular diseases, particularly those diseases related tothrombosis.

DESCRIPTION OF THE RELATED ART

[0002] Thrombotic complications are a major cause of death in theindustrialized world. Examples of these complications include acutemyocardial infarction, unstable angina, chronic stable angina, transientischemic attacks, strokes, peripheral vascular disease,preeclampsia/eclampsia, deep venous thrombosis, embolism, disseminatedintravascular coagulation and thrombotic cytopenic purpura. Thromboticand restenotic complications also occur following invasive procedures,e.g., angioplasty, carotid endarterectomy, post CABG (coronary arterybypass graft) surgery, vascular graft surgery, stent placements andinsertion of endovascular devices and protheses. It is generally thoughtthat platelet aggregates play a critical role in these events. Bloodplatelets, which normally circulate freely in the vasculature, becomeactivated and aggregate to form a thrombus with disturbed blood flowcaused by ruptured atherosclerotic lesions or by invasive treatmentssuch as angioplasty, resulting in vascular occlusion. Plateletactivation can be initiated by a variety of agents, e.g., exposedsubendothelial matrix molecules such as collagen, or by thrombin whichis formed in the coagulation cascade.

[0003] An important mediator of platelet activation and aggregation isADP (adenosine 5′-diphosphate) which is released from blood platelets inthe vasculature upon activation by various agents, such as collagen andthrombin, and from damaged blood cells, endothelium or tissues.Activation by ADP results in the recruitment of more platelets andstabilization of existing platelet aggregates. Platelet ADP receptorsmediating aggregation are activated by ADP and some of its derivativesand antagonized by ATP (adenosine 5′-triphosphate) and some of itsderivatives (Mills, D. C. B. (1996) Thromb. Hemost. 76:835-856).Therefore, platelet ADP receptors are members of the family of P2receptors activated by purine and/or pyrimidine nucleotides (King, B.F., Townsend-Nicholson, A. & Burnstock, G. (1998) Trends Pharmacol Sci.19:506-514).

[0004] Recent pharmacological data using selective antagonists suggeststhat ADP-dependent platelet aggregation requires activation of at leasttwo ADP receptors (Kunapuli, S. P. (1998), Trends Pharmacol Sci.19:391-394; Kunapuli, S. P. & Daniel, J. L. (1998) Biochem. J.336:513-523; Jantzen, H. M. et al. (1999) Thromb. Hemost. 81:111-117).One receptor appears to be identical to the cloned P2Y₁ receptor,mediates phospholipase C activation and intracellular calciummobilization and is required for platelet shape change. The secondplatelet ADP receptor important for aggregation mediates inhibition ofadenylyl cyclase. Molecular cloning of the gene or cDNA for thisreceptor has not yet been reported. Based on its pharmacological andsignaling properties this receptor has been provisionally termedP2Y_(ADP) (Fredholm, B. B. et al. (1997) TIPS 18:79-82), P2T_(AC)(Kunapuli, S. P. (1998), Trends Pharmacol. Sci. 19:391-394) or P2Ycyc(Hechler, B. et al. (1998) Blood 92, 152-159).

[0005] Various directly or indirectly acting synthetic inhibitors ofADP-dependent platelet aggregation with antithrombotic activity havebeen reported. The orally active antithrombotic thienopyridinesticlopidine and clopidogrel inhibit ADP-induced platelet aggregation,binding of radiolabeled ADP receptor agonist 2-methylthioadenosine5′-diphosphate to platelets, and other ADP-dependent events indirectly,probably via formation of an unstable and irreversible acting metabolite(Quinn, M. J. & Fitzgerald, D. J. (1999) Circulation 100:1667-1667).Some purine derivatives of the endogenous antagonist ATP, e.g., AR-C(formerly FPL or ARL) 67085MX and AR-C69931MX, are selective plateletADP receptor antagonists which inhibit ADP-dependent plateletaggregation and are effective in animal thrombosis models (Humphries etal. (1995), Trends Pharmacol. Sci. 16, 179; Ingall, A. H. et al. (1999)J. Med. Chem. 42, 213-230). Novel triazolo [4,5-d] pyrimidine compoundshave been disclosed as P_(2T)-antagonists (WO 99/05144). Tricycliccompounds as platelet ADP receptor inhibitors have also been disclosedin WO 99/36425. The target of these antithrombotic compounds appears tobe the platelet ADP receptor mediating inhibition of adenylyl cyclase.

[0006] Despite these compounds, there exists a need for more effectiveplatelet ADP receptor inhibitors. In particular, there is a need forplatelet ADP receptor inhibitors having antithrombotic activity that areuseful in the prevention and/or treatment of cardiovascular diseases,particularly those related to thrombosis.

SUMMARY OF THE INVENTION

[0007] The invention provides compounds of formula (I), formula (II),formula (III), formula (IV), formula (V) and formula (VI):

[0008] A is selected from the group consisting of aryl, substitutedaryl, heteroaryl, substituted heteroaryl, alkylaryl, andalkylheteroaryl.

[0009] W is selected from the group consisting of aryl, substitutedaryl, heteroaryl, and substituted heteroaryl.

[0010] E is selected from the group consisting of H, —C₁-C₈ alkyl,polyhaloalkyl, —C₃₋₈-cycloalkyl, aryl, alkylaryl, substituted aryl,heteroaryl, and substituted heteroaryl.

[0011] D is selected from the group consisting of

[0012] wherein:

[0013] R¹ is independently selected from the group consisting of:

[0014] H, C₁-C₈ alkyl, polyhaloalkyl, —C₃₋₈-cycloalkyl, aryl, alkylaryl,substituted aryl, heteroaryl, substituted heteroaryl, —(C—O)—C₁-C₈alkyl, —(C═O)-aryl, —(C═O)-substituted aryl, —(C═O)-heteroaryl and—(C═O)-substituted heteroaryl;

[0015] R² is independently selected from the group consisting of aryl,substituted aryl, heteroaryl, substituted heteroaryl, or

[0016] R¹ and R² can be direct linked or can be indirectly linkedthrough a carbon chain that is from 1 to about 8 carbon atoms in length,

[0017] n is 0-4,

[0018] m is 0 or 1,

[0019] y is 0-4 and

[0020] Q is independently C or N, with the proviso that when Q is a ringcarbon atom, each ring carbon atom is independenty substituted by X.

[0021] X is in each case a member independently selected from the groupconsisting of:

[0022] H, halogen, polyhaloalkyl, —OR³, —SR³, —CN, —NO₂, —SO₂R³,—C₁₋₁₀-alkyl, —C₃₋₈-cycloalkyl, aryl, aryl-substituted by 1-4 R³ groups,amino, amino-C₁₋₈-alkyl, C₁₋₃-acylamino, C₁₋₃-acylamino-C₁₋₈-alkyl,C₁₋₆-alkylamino, C₁₋₆-alkylamino C₁₋₈ alkyl, C₁₋₆ dialkylamino, C₁₋₆dialkylamino C₁₋₈ alkyl, C₁₋₆ alkoxy, C₁₋₆ alkoxy-C₁₋₆-alkyl,carboxy-C₁₋₆-alkyl, C₁₋₃-alkoxycarbonyl, C₁₋₃-alkoxycarbonyl-C₁₋₆-alkyl,carboxy C₁₋₆ alkyloxy, hydroxy, hydroxy C₁₋₆ alkyl, and a 5 to 10membered fused or non-fused aromatic or nonaromatic heterocyclic ringsystem, having 1 to 4 heteroatoms independently selected from N, O, andS, with the proviso that the carbon and nitrogen atoms, when present inthe heterocyclic ring system, are unsubstituted, mono- or di-substitutedindependently with 0-2 R⁴ groups.

[0023] R³ and R⁴ are each independently selected from the groupconsisting of: H, halogen, —CN, —NO₂, —C₁₋₁₀ alkyl, C₃₋₈-cycloalkyl,aryl, amino, amino-C₁₋₈-alkyl, C₁₋₃-acylamino,C₁₋₃-acylamino-C₁₋₈-alkyl, C₁₋₆-alkylamino, C₁₋₆-alkylamino C₁₋₈ alkyl,C₁₋₆ dialkylamino, C₁₋₆ dialkylamino C₁₋₈ alkyl, C₁₋₆ alkoxy, C₁₋₆alkoxy-C₁₋₆-alkyl, carboxy-C₁₋₆-alkyl, C₁₋₃-alkoxycarbonyl,C₁₋₃-alkoxycarbonyl-C₁₋₆-alkyl, carboxy-C₁₋₆-alkyloxy, hydroxy,hydroxy-C₁₋₆-alkyl, -thio and thio-C₁₋₆-alkyl.

[0024] Y is selected from the group consisting of O, S, N—OR⁵, and NR⁵,

[0025] wherein R⁵ is selected from the group consisting of:

[0026] H, C₁₋₁₀ alkyl, C₃₋₈-cycloalkyl, and CN.

[0027] The invention also covers all pharmaceutically acceptable saltsand prodrugs of the compounds of formulae (I)-(VI).

[0028] In another aspect, the invention provides pharmaceuticalcompositions for preventing or treating thrombosis in a mammalcontaining a therapeutically effective amount of a compound of formulae(I)-(VI) or a pharmaceutically acceptable salt thereof and apharmaceutically acceptable carrier. The invention further provides amethod for preventing or treating thrombosis in a mammal byadministering a therapeutically effective amount of a compound offormulae (I)-(VI) or a pharmaceutically acceptable salt thereof.

DETAILED DESCRIPTION OF THE INVENTION

[0029] Definitions

[0030] In accordance with the present invention and as used herein, thefollowing terms are defined with the following meanings, unlessexplicitly stated otherwise.

[0031] The term “alkenyl” refers to a trivalent straight chain orbranched chain unsaturated aliphatic radical. The term “alkinyl” (or“alkynyl”) refers to a straight or branched chain aliphatic radical thatincludes at least two carbons joined by a triple bond. If no number ofcarbons is specified, alkenyl and alkinyl each refer to radicals havingfrom 2-12 carbon atoms.

[0032] The term “alkyl” refers to saturated aliphatic groups includingstraight-chain, branched-chain and cyclic groups having the number ofcarbon atoms specified, or if no number is specified, having up to about12 carbon atoms. The term “cycloalkyl” as used herein refers to a mono-,bi-, or tricyclic aliphatic ring having 3 to about 14 carbon atoms andpreferably 3 to about 7 carbon atoms.

[0033] The term “C₁-C₆ alkoxy” as used herein refers to an ether moietywhereby the oxygen is connected to a straight or branched chain ofcarbon atoms of the number indicated.

[0034] The term “mono-C₁-C₆ alkylamino” as used herein refers to anamino moiety whereby the nitrogen is substituted with one H and oneC₁-C₆ alkyl substituent, the latter being defined as above.

[0035] The term “di-C₁-C₆ alkylamino” as used herein refers to an aminomoiety whereby the nitrogen is substituted with two C₁-C₆ alkylsubstituents as defined above.

[0036] The term “monoarylamino” as used herein refers to an amino moietywhereby the nitrogen is substituted with one H and one aryl substituent,such as a phenyl, the latter being defined as above.

[0037] The term “diarylamino” as used herein refers to an amino moietywhereby the nitrogen is substituted with two aryl substituents, such asphenyl, the latter being defined as above.

[0038] The term “C₁-C₆ alkylsulfonyl” as used herein refers to adioxosulfur moiety with the sulfur atom also connected to one C₁-C₆alkyl substituent, the latter being defined as above.

[0039] The term “C₁-C₆ alkoxycarbonyl” as used herein refers to ahydroxycarbonyl moiety whereby the hydrogen is replaced by a C₁-C₆ alkylsubstituent, the latter being defined as above.

[0040] As used herein, the terms “carbocyclic ring structure” and “C₃₋₁₆carbocyclic mono, bicyclic or tricyclic ring structure” or the like areeach intended to mean stable ring structures having only carbon atoms asring atoms wherein the ring structure is a substituted or unsubstitutedmember selected from the group consisting of: a stable monocyclic ringwhich is an aromatic ring (“aryl”) having six ring atoms (“phenyl”); astable monocyclic non-aromatic ring having from 3 to about 7 ring atomsin the ring; a stable bicyclic ring structure having a total of from 7to about 12 ring atoms in the two rings wherein the bicyclic ringstructure is selected from the group consisting of ring structures inwhich both of the rings are aromatic, ring structures in which one ofthe rings is aromatic and ring structures in which both of the rings arenon-aromatic; and a stable tricyclic ring structure having a total offrom about 10 to about 16 atoms in the three rings wherein the tricyclicring structure is selected from the group consisting of: ring structuresin which three of the rings are aromatic, ring structures in which twoof the rings are aromatic and ring structures in which three of therings are non-aromatic. In each case, the non-aromatic rings whenpresent in the monocyclic, bicyclic or tricyclic ring structure mayindependently be saturated, partially saturated or fully saturated.Examples of such carbocyclic ring structures include, but are notlimited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, adamantyl,cyclooctyl, [3.3.0]bicyclooctane, [4.3.0]bicyclononane,[4.4.0]bicyclodecane (decalin), [2.2.2]bicyclooctane, fluorenyl, phenyl,naphthyl, indanyl, adamantyl, or tetrahydronaphthyl (tetralin).Moreover, the ring structures described herein may be attached to one ormore indicated pendant groups via any carbon atom which results in astable structure. The term “substituted” as used in conjunction withcarbocyclic ring structures means that hydrogen atoms attached to thering carbon atoms of ring structures described herein may be substitutedby one or more of the substituents indicated for that structure if suchsubstitution(s) would result in a stable compound.

[0041] The term “aryl” which is included with the term “carbocyclic ringstructure” refers to an unsubstituted or substituted aromatic ring,substituted with one, two or three substituents selected from loweralkoxy, lower alkyl, lower alkylamino, hydroxy, halogen, cyano,hydroxyl, mercapto, nitro, thioalkoxy, carboxaldehyde, carboxyl,carboalkoxy and carboxamide, including but not limited to carbocyclicaryl, heterocyclic aryl, and biaryl groups and the like, all of whichmay be optionally substituted. Preferred aryl groups include phenyl,halophenyl, loweralkylphenyl, napthyl, biphenyl, phenanthrenyl andnaphthacenyl.

[0042] The term “arylalkyl” which is included with the term “carbocyclicaryl” refers to one, two, or three aryl groups having the number ofcarbon atoms designated, appended to an alkyl group having the number ofcarbon atoms designated. Suitable arylalkyl groups include, but are notlimited to, benzyl, picolyl, naphthylmethyl, phenethyl, benzyhydryl,trityl, and the like, all of which may be optionally substituted.

[0043] The term “phenyl” as used herein refers to a six carboncontaining aromatic ring which can be variously mono- orpoly-substituted with H, C₁-C₆ alkyl, hydroxyl, C₁-C₆ alkoxy, amino,mono-C₁-C₆ alkylamino, di-C₁-C₆ alkylamino, nitro, fluoro, chloro,bromo, iodo, hydroxycarbonyl, or C₁-C₆ alkoxycarbonyl.

[0044] As used herein, the term “heterocyclic ring” or “heterocyclicring system” is intended to mean a substituted or unsubstituted memberselected from the group consisting of a stable monocyclic ring havingfrom 5-7 members in the ring itself and having from 1 to 4 hetero ringatoms selected from the group consisting of N, O and S; a stablebicyclic ring structure having a total of from 7 to 12 atoms in the tworings wherein at least one of the two rings has from 1 to 4 hetero atomsselected from N, O and S, including bicyclic ring structures wherein anyof the described stable monocyclic heterocyclic rings is fused to ahexane or benzene ring; and a stable tricyclic heterocyclic ringstructure having a total of from 10 to 16 atoms in the three ringswherein at least one of the three rings has from 1 to 4 hetero atomsselected from the group consisting of N, O and S. Any nitrogen andsulfur atoms present in a heterocyclic ring of such a heterocyclic ringstructure may be oxidized. Unless indicated otherwise the terms“heterocyclic ring” or “heterocyclic ring system” include aromaticrings, as well as non-aromatic rings which can be saturated, partiallysaturated or fully saturated non-aromatic rings. Also, unless indicatedotherwise the term “heterocyclic ring system” includes ring structureswherein all of the rings contain at least one hetero atom as well asstructures having less than all of the rings in the ring structurecontaining at least one hetero atom, for example bicyclic ringstructures wherein one ring is a benzene ring and one of the rings hasone or more hetero atoms are included within the term “heterocyclic ringsystems” as well as bicyclic ring structures wherein each of the tworings has at least one hetero atom. Moreover, the ring structuresdescribed herein may be attached to one or more indicated pendant groupsvia any hetero atom or carbon atom which results in a stable structure.Further, the term “substituted” means that one or more of the hydrogenatoms on the ring carbon atom(s) or nitrogen atom(s) of the each of therings in the ring structures described herein may be replaced by one ormore of the indicated substituents if such replacement(s) would resultin a stable compound. Nitrogen atoms in a ring structure may bequaternized, but such compounds are specifically indicated or areincluded within the term “a pharmaceutically acceptable salt” for aparticular compound. When the total number of O and S atoms in a singleheterocyclic ring is greater than 1, it is preferred that such atoms notbe adjacent to one another. Preferably, there are no more that 1 O or Sring atoms in the same ring of a given heterocyclic ring structure.

[0045] Examples of monocylic and bicyclic heterocylic ring systems, inalphabetical order, are acridinyl, azocinyl, benzimidazolyl,benzofuranyl, benzothiofuranyl, benzothiophenyl, benzoxazolyl,benzthiazolyl, benztriazolyl, benztetrazolyl, benzisoxazolyl,benzisothiazolyl, benzimidazalinyl, carbazolyl, 4aH-carbazolyl,carbolinyl, chromanyl, chromenyl, cinnolinyl, decahydroquinolinyl,2H,6H-1,5,2-dithiazinyl, dihydrofuro[2,3-b]tetrahydrofuran, furanyl,furazanyl, imidazolidinyl, imidazolinyl, imidazolyl, 1H-indazolyl,indolinyl, indolizinyl, indolyl, 3H-indolyl, isobenzofuranyl,isochromanyl, isoindazolyl, isoindolinyl, isoindolyl, isoquinolinyl(benzimidazolyl), isothiazolyl, isoxazolyl, morpholinyl, naphthyridinyl,octahydroisoquinolinyl, oxadiazolyl, 1,2,3-oxadiazolyl,1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, oxazolidinyl,oxazolyl, oxazolidinyl, pyrimidinyl, phenanthridinyl, phenanthrolinyl,phenazinyl, phenothiazinyl, phenoxathiinyl, phenoxazinyl, phthalazinyl,piperazinyl, piperidinyl, pteridinyl, purinyl, pyranyl, pyrazinyl,pyroazolidinyl, pyrazolinyl, pyrazolyl, pyridazinyl, pryidooxazole,pyridoimidazole, pyridothiazole, pyridinyl, pyridyl, pyrimidinyl,pyrrolidinyl, pyrrolinyl, 2H-pyrrolyl, pyrrolyl, quinazolinyl,quinolinyl, 4H-quinolizinyl, quinoxalinyl, quinuclidinyl,tetrahydrofuranyl, tetrahydroisoquinolinyl, tetrahydroquinolinyl,6H-1,2,5-thiadazinyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl,1,2,5-thiadiazolyl, 1,3,4-thiadiazolyl, thianthrenyl, thiazolyl,thienyl, thienothiazolyl, thienooxazolyl, thienoimidazolyl, thiophenyl,triazinyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1,2,5-triazolyl,1,3,4-triazolyl and xanthenyl. Preferred heterocyclic ring structuresinclude, but are not limited to, pyridinyl, furanyl, thienyl, pyrrolyl,pyrazolyl, pyrrolidinyl, imidazolyl, indolyl, benzimidazolyl,1H-indazolyl, oxazolinyl, or isatinoyl. Also included are fused ring andspiro compounds containing, for example, the above heterocylic ringstructures.

[0046] As used herein the term “aromatic heterocyclic ring system” hasessentially the same definition as for the monocyclic and bicyclic ringsystems except that at least one ring of the ring system is an aromaticheterocyclic ring or the bicyclic ring has an aromatic or non-aromaticheterocyclic ring fused to an aromatic carbocyclic ring structure.

[0047] The terms “halo” or “halogen” as used herein refer to Cl, Br, For I substituents. The term “haloalkyl”, and the like, refer to analiphatic carbon radicals having at least one hydrogen atom replaced bya Cl, Br, F or I atom, including mixtures of different halo atoms.Trihaloalkyl includes trifluoromethyl and the like as preferredradicals, for example.

[0048] The term “methylene” refers to —CH₂—.

[0049] The term “pharmaceutically acceptable salts” includes salts ofcompounds derived from the combination of a compound and an organic orinorganic acid. These compounds are useful in both free base and saltform. In practice, the use of the salt form amounts to use of the baseform; both acid and base addition salts are within the scope of thepresent invention.

[0050] “Pharmaceutically acceptable acid addition salt” refers to saltsretaining the biological effectiveness and properties of the free basesand which are not biologically or otherwise undesirable, formed withinorganic acids such as hydrochloric acid, hydrobromic acid, sulfuricacid, nitric acid, phosphoric acid and the like, and organic acids suchas acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalicacid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaricacid, citric acid, benzoic acid, cinnamic acid, mandelic acid,methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid,salicyclic acid and the like.

[0051] “Pharmaceutically acceptable base addition salts” include thosederived from inorganic bases such as sodium, potassium, lithium,ammonium, calcium, magnesium, iron, zinc, copper, manganese, aluminumsalts and the like. Particularly preferred are the ammonium, potassium,sodium, calcium and magnesium salts. Salts derived from pharmaceuticallyacceptable organic nontoxic bases include salts of primary, secondary,and tertiary amines, substituted amines including naturally occurringsubstituted amines, cyclic amines and basic ion exchange resins, such asisopropylamine, trimethylamine, diethylamine, triethylamine,tripropylamine, ethanolamine, 2-diethylaminoethanol, trimethamine,dicyclohexylamine, lysine, arginine, histidine, caffeine, procaine,hydrabamine, choline, betaine, ethylenediamine, glucosamine,methylglucamine, theobromine, purines, piperizine, piperidine,N-ethylpiperidine, polyamine resins and the like. Particularly preferredorganic nontoxic bases are isopropylamine, diethylamine, ethanolamine,trimethamine, dicyclohexylamine, choline, and caffeine.

[0052] “Biological property” for the purposes herein means an in vivoeffector or antigenic function or activity that is directly orindirectly performed by a compound of this invention that are oftenshown by in vitro assays. Effector functions include receptor or ligandbinding, any enzyme activity or enzyme modulatory activity, any carrierbinding activity, any hormonal activity, any activity in promoting orinhibiting adhesion of cells to an extracellular matrix or cell surfacemolecules, or any structural role. Antigenic functions includepossession of an epitope or antigenic site that is capable of reactingwith antibodies raised against it.

[0053] In the compounds of this invention, carbon atoms bonded to fournon-identical substituents are asymmetric. Accordingly, the compoundsmay exist as diastereoisomers, enantiomers or mixtures thereof. Thesyntheses described herein may employ racemates, enantiomers ordiastereomers as starting materials or intermediates. Diastereomericproducts resulting from such syntheses may be separated bychromatographic or crystallization methods, or by other methods known inthe art. Likewise, enantiomeric product mixtures may be separated usingthe same techniques or by other methods known in the art. Each of theasymmetric carbon atoms, when present in the compounds of thisinvention, may be in one of two configurations (R or S) and both arewithin the scope of the present invention.

[0054] Compound Embodiments of the Invention

[0055] Compounds of formula (I), formula (II), formula (III), formula(IV), formula (V) and formula (VI) below represent one embodiment of theinvention:

[0056] A is selected from the group consisting of aryl, substitutedaryl, heteroaryl, substituted heteroaryl, alkylaryl, andalkylheteroaryl.

[0057] W is selected from the group consisting of aryl, substitutedaryl, heteroaryl, and substituted heteroaryl.

[0058] E is selected from the group consisting of H, —C₁-C₈ alkyl,polyhaloalkyl, —C₃₋₈-cycloalkyl, aryl, alkylaryl, substituted aryl,heteroaryl, and substituted heteroaryl.

[0059] D is selected from the group consisting of NR¹—(C═O)—R², —O—R¹;

[0060] wherein:

[0061] R¹ is independently selected from the group consisting of:

[0062] H, C₁-C₈ alkyl, polyhaloalkyl, —C₃₋₈-cycloalkyl, aryl, alkylaryl,substituted aryl, heteroaryl, substituted heteroaryl, —(C═O)-C₁-C₈alkyl, —(C═O)-aryl, —(C═O)-substituted aryl, —(C═O)-heteroaryl and—(C═O)-substituted heteroaryl;

[0063] R² is selected from the group consisting of: aryl, substitutedaryl, heteroaryl, substituted heteroaryl, or

[0064] R¹ and R² can be direct linked or can be indirectly linkedthrough a carbon chain that is from 1 to about 8 carbon atoms in length,

[0065] n is 0-4,

[0066] m is 0 or 1,

[0067] y is 0-4 and

[0068] Q is independently C or N, with the proviso that when Q is a ringcarbon atom, each ring carbon atom is independently substituted by X,wherein

[0069] X is in each case a member independently selected from the groupconsisting of:

[0070] H, halogen, polyhaloalkyl, —OR³, —SR³, —CN, —NO₂, —SO₂R³,—C₁₋₁₀-alkyl, —C₃₋₈-cycloalkyl, aryl, aryl-substituted by 1-4 R³ groups,amino, amino-C₁₋₈-alkyl, C₁₋₃-acylamino, C₁₋₃-acylamino-C₁₋₈-alkyl,C₁₋₆-alkylamino, C₁₋₆-alkylamino C₁₋₈ alkyl, C₁₋₆ dialkylamino, C₁₋₆dialkylamino C₁₋₈ alkyl, C₁₋₆ alkoxy, C₁₋₆ alkoxy-C₁₋₆-alkyl,carboxy-C₁₋₆-alkyl, C₁₋₃-alkoxycarbonyl, C₁₋₃-alkoxycarbonyl-C₁₋₆-alkyl,carboxy C₁₋₆ alkyloxy, hydroxy, hydroxy C₁₋₆ alkyl, and a 5 to 10membered fused or non-fused aromatic or nonaromatic heterocyclic ringsystem, having 1 to 4 heteroatoms independently selected from N, O, andS, with the proviso that the carbon and nitrogen atoms, when present inthe heterocyclic ring system, are unsubstituted, mono- or di-substitutedindependently with 0-2 R⁴ groups, and

[0071] wherein R³ and R⁴ are each independently selected from the groupconsisting of:

[0072] H, halogen, —CN, —NO₂, —C₁₋₁₀ alkyl, C₃₋₈-cycloalkyl, aryl,amino, amino-C₁₋₈-alkyl, C₁₋₃-acylamino, C₁₋₃-acylamino-C₁₋₈-alkyl,C₁₋₆-alkylamino, C₁₋₆-alkylamino C₁₋₈ alkyl, C₁₋₆ dialkylamino, C₁₋₆dialkylamino C₁₋₈ alkyl, C₁₋₆ alkoxy, C₁₋₆ alkoxy-C₁₋₆-alkyl,carboxy-C₁₋₆-alkyl, C₁₋₃-alkoxycarbonyl, C₁₋₃-alkoxycarbonyl-C₁₋₆-alkyl,carboxy-C₁₋₆-alkyloxy, hydroxy, hydroxy-C₁₋₆-alkyl, -thio andthio-C₁₋₆-alkyl.

[0073] Y is selected from the group consisting of O, S, N—OR⁵, and NR⁵,

[0074] wherein R is selected from the group consisting of:

[0075] H, C₁₋₁₀ alkyl, C₃₋₈-cycloalkyl, and CN.

[0076] The invention also covers all pharmaceutically acceptable saltsand prodrugs of the compounds of formula I to formula VI.

[0077] In another preferred embodiment of the invention, compounds offormulae (I)-(VI) include the compounds set forth below in Tables 1-4:TABLE 1

R₂ R₁ W Y A

H

O

H

O

H

S

H

N—C≡N

H

O

H

NH

Me

NH

N—C≡N

Me

O

H

O

H

[0078] TABLE 2

X W Y A 3-Br

O

3-Cl

NH

4-OMe

O

H

N—C≡N

3,4-diMe

NH

3-SO₂Me

O

[0079] TABLE 3

Y A O

NH

O

N—C≡N

NH

O

[0080] TABLE 4

R₁ R₂ W H

Me

H

H

Me

H

[0081] Examples of specific preferred compounds are listed below:

[0082] Preparation of Compounds of the Invention

[0083] A compound of formulae (I)-(VI) may be prepared by variousmethods as outlined in the following documents: J. Med. Chem., 33,23-93-2407 (1990); Biorg. & Med. Chem. Letts., Vol. 2, No. 9, pp.987-992 (1992); J. Med. Chem., 35, 3012-3016 (1992); U.S. Pat. No.5,234,955 (1993), U.S. Pat. No. 5,354,778 (1994); U.S. Pat. No.5,565,494 (1996); U.S. Pat. No. 5,594,028 (1997); U.S. Pat. No.5,302,724 (1994); and WO 97/08145, which are incorporated herein intheir entirety by reference. Other well-known heterocyclic andcarbocyclic synthetic procedures as well as modification of theprocedures that are incorporated above may be utilized.

[0084] Compounds of formulae (I)-(VI) may be isolated using typicalisolation and purification techniques known in the art, including, forexample, chromatographic and recrystallization methods.

[0085] In compounds of formula formulae (I)-(VI) of the invention,carbon atoms to which four non-identical substituents are bonded areasymmetric. Accordingly, a compound of formulae (I)-(VI) may exist asenantiomers, diastereomers or a mixture thereof. The enantiomers anddiastereomers may be separated by chromatographic or crystallizationmethods, or by other methods known in the art. The asymmetric carbonatom when present in a compound of formulae (I)-(VI) of the invention,may be in one of two configurations (R or S) and both are within thescope of the invention. The presence of small amounts of the opposingenantiomer or diastereomer in the final purified product does not affectthe therapeutic or diagnostic application of such compounds.

[0086] According to the invention, compounds of formulae (I)-(VI) may befurther treated to form pharmaceutically acceptable salts. Treatment ofa compound of the invention with an acid or base may form, respectively,a pharmaceutically acceptable acid addition salt and a pharmaceuticallyacceptable base addition salt, each as defined above. Various inorganicand organic acids and bases known in the art including those definedherein may be used to effect the conversion to the salt.

[0087] The invention also relates to pharmaceutically acceptableisomers, hydrates, and solvates of compounds of formulae (I)-(VI).Compounds of formulae (I)-(VI) may also exist in various isomeric andtautomeric forms including pharmaceutically acceptable salts, hydratesand solvates of such isomers and tautomers.

[0088] This invention also encompasses prodrug derivatives of thecompounds of formulae (I)-(VI). The term “prodrug” refers to apharmacologically inactive derivative of a parent drug molecule thatrequires biotransformation, either spontaneous or enzymatic, within theorganism to release the active drug. Prodrugs are variations orderivatives of the compounds of formulae (I)-(VI) of this inventionwhich have groups cleavable under metabolic conditions. Prodrugs becomethe compounds of the invention which are pharmaceutically active in vivowhen they undergo solvolysis under physiological conditions or undergoenzymatic degradation. Prodrug compounds of this invention may be calledsingle, double, triple, etc., depending on the number ofbiotransformation steps required to release the active drug within theorganism, and indicating the number of functionalities present in aprecursor-type form. Prodrug forms often offer advantages of solubility,tissue compatibility, or delayed release in the mammalian organism(Bundgard, Design of Prodrugs, pp. 7-9, 21-24, Elsevier, Amsterdam(1985); Silverman, The Organic Chemistry of Drug Design and Drug Action,pp. 352-401, Academic Press, San Diego, Calif. (1992)). Prodrugscommonly known in the art include acid derivatives well known topractitioners of the art, such as, for example, esters prepared byreaction of the parent acids with a suitable alcohol, or amides preparedby reaction of the parent acid compound with an amine, or basic groupsreacted to form an acylated base derivative. Moreover, the prodrugderivatives of this invention may be combined with other features hereintaught to enhance bioavailability.

[0089] Pharmaceutical Compositions and Methods of Treatment

[0090] A compound of formulae (I)-(VI) according to the invention may beformulated into pharmaceutical compositions. Accordingly, the inventionalso relates to a pharmaceutical composition for preventing or treatingthrombosis in a mammal, particularly those pathological conditionsinvolving platelet aggregation, containing a therapeutically effectiveamount of a compound of formulae (I)-(VI) or a pharmaceuticallyacceptable salt thereof, each as described above, and a pharmaceuticallyacceptable carrier or agent. Preferably, a pharmaceutical composition ofthe invention contains a compound of formulae (I)-(VI), or a saltthereof, in an amount effective to inhibit platelet aggregation, morepreferably, ADP-dependent aggregation, in a mammal, in particular, ahuman. Pharmaceutically acceptable carriers or agents include thoseknown in the art and are described below.

[0091] Pharmaceutical compositions of the invention may be prepared bymixing the compound of formulae (I)-(VI) with a physiologicallyacceptable carrier or agent. Pharmaceutical compositions of theinvention may further include excipients, stabilizers, diluents and thelike and may be provided in sustained release or timed releaseformulations. Acceptable carriers, agents, excipients, stablilizers,diluents and the like for therapeutic use are well known in thepharmaceutical field, and are described, for example, in Remington'sPharmaceutical Sciences, Mack Publishing Co., ed. A. R. Gennaro (1985).Such materials are nontoxic to the recipients at the dosages andconcentrations employed, and include buffers such as phosphate, citrate,acetate and other organic acid salts, antioxidants such as ascorbicacid, low molecular weight (less than about ten residues) peptides suchas polyarginine, proteins, such as serum albumin, gelatin, orimmunoglobulins, hydrophilic polymers such as polyvinylpyrrolidinone,amino acids such as glycine, glutamic acid, aspartic acid, or arginine,monosaccharides, disaccharides, and other carbohydrates includingcellulose or its derivatives, glucose, mannose or dextrins, chelatingagents such as EDTA, sugar alcohols such as mannitol or sorbitol,counterions such as sodium and/or nonionic surfactants such as TWEEN, orpolyethyleneglycol.

[0092] Methods for preventing or treating thrombosis in a mammalembraced by the invention administer a therapeutically effective amountof a compound of formulae (I)-(VI) alone or as part of a pharmaceuticalcomposition of the invention as described above to a mammal, inparticular, a human. Compounds of formulae (I)-(VI) and pharmaceuticalcompositions of the invention containing a compound of formulae (I)-(VI)of the invention are suitable for use alone or as part of amulti-component treatment regimen for the prevention or treatment ofcardiovascular diseases, particularly those related to thrombosis. Forexample, a compound or pharmaceutical composition of the invention maybe used as a drug or therapeutic agent for any thrombosis, particularlya platelet-dependent thrombotic indication, including, but not limitedto, acute myocardial infarction, unstable angina, chronic stable angina,transient ischemic attacks, strokes, peripheral vascular disease,preeclampsia/eclampsia, deep venous thrombosis, embolism, disseminatedintravascular coagulation and thrombotic cytopenic purpura, thromboticand restenotic complications following invasive procedures, e.g.,angioplasty, carotid endarterectomy, post CABG (coronary artery bypassgraft) surgery, vascular graft surgery, stent placements and insertionof endovascular devices and protheses.

[0093] Compounds and pharmaceutical compositions of the invention mayalso be used as part of a multi-component treatment regimen incombination with other therapeutic or diagnostic agents in theprevention or treatment of thrombosis in a mammal. In certain preferredembodiments, compounds or pharmaceutical compositions of the inventionmay be coadministered along with other compounds typically prescribedfor these conditions according to generally accepted medical practicesuch as anticoagulant agents, thrombolytic agents, or otherantithrombotics, including platelet aggregation inhibitors, tissueplasminogen activators, urokinase, prourokinase, streptokinase, heparin,aspirin, or warfarin. Coadministration may also allow for application ofreduced doses of the thrombolytic agents and therefore minimizepotential hemorrhagic side-effects. Compounds and pharmaceuticalcompositions of the invention may also act in a synergistic fashion toprevent reocclusion following a successful thrombolytic therapy and/orreduce the time to reperfusion.

[0094] The compounds and pharmaceutical compositions of the inventionmay be utilized in vivo, ordinarily in mammals such as primates, (e.g.,humans), sheep, horses, cattle, pigs, dogs, cats, rats and mice, or invitro. The biological properties, as defined above, of a compound or apharmaceutical composition of the invention can be readily characterizedby methods that are well known in the art such as, for example, by invivo studies to evaluate antithrombotic efficacy, and effects onhemostasis and hematological parameters.

[0095] Compounds and pharmaceutical compositions of the invention may bein the form of solutions or suspensions. In the management of thromboticdisorders the compounds or pharmaceutical compositions of the inventionmay also be in such forms as, for example, tablets, capsules or elixirsfor oral administration, suppositories, sterile solutions or suspensionsor injectable administration, and the like, or incorporated into shapedarticles. Subjects (typically mammalian) in need of treatment using thecompounds or pharmaceutical compositions of the invention may beadministered dosages that will provide optimal efficacy. The dose andmethod of administration will vary from subject to subject and bedependent upon such factors as the type of mammal being treated, itssex, weight, diet, concurrent medication, overall clinical condition,the particular compound of formulae (I)-(VI) employed, the specific usefor which the compound or pharmaceutical composition is employed, andother factors which those skilled in the medical arts will recognize.

[0096] Dosage formulations of compounds of formulae (I)-(VI), orpharmaceutical compositions contain a compound of the invention, to beused for therapeutic administration must be sterile. Sterility isreadily accomplished by filtration through sterile membranes such as 0.2micron membranes, or by other conventional methods. Formulationstypically will be stored in a solid form, preferably in a lyophilizedform. While the preferred route of administration is orally, the dosageformulations of compounds of formulae (I)-(VI) or pharmaceuticalcompositions of the invention may also be administered by injection,intravenously (bolus and/or infusion), subcutaneously, intramuscularly,colonically, rectally, nasally, transdermally or intraperitoneally. Avariety of dosage forms may be employed as well including, but notlimited to, suppositories, implanted pellets or small cylinders,aerosols, oral dosage formulations and topical formulations such asointments, drops and dermal patches. The compounds of formulae (I)-(VI)and pharmaceutical compositions of the invention may also beincorporated into shapes and articles such as implants which may employinert materials such biodegradable polymers or synthetic silicones as,for example, SILASTIC, silicone rubber or other polymers commerciallyavailable. The compounds and pharmaceutical compositions of theinvention may also be administered in the form of liposome deliverysystems, such as small unilamellar vesicles, large unilamellar vesiclesand multilamellar vesicles. Liposomes can be formed from a variety oflipids, such as cholesterol, stearylamine or phosphatidylcholines.

[0097] Therapeutically effective dosages may be determined by either invitro or in vivo methods. For each particular compound or pharmaceuticalcomposition of the invention, individual determinations may be made todetermine the optimal dosage required. The range of therapeuticallyeffective dosages will be influenced by the route of administration, thetherapeutic objectives and the condition of the patient. For injectionby hypodermic needle, it may be assumed the dosage is delivered into thebodily fluids. For other routes of administration, the absorptionefficiency must be individually determined for each compound by methodswell known in pharmacology. Accordingly, it may be necessary for thetherapist to titer the dosage and modify the route of administration asrequired to obtain the optimal therapeutic effect.

[0098] The determination of effective dosage levels, that is, the dosagelevels necessary to achieve the desired result, i.e., platelet ADPreceptor inhibition, will be readily determined by one skilled in theart. Typically, applications of a compound or pharmaceutical compositionof the invention are commenced at lower dosage levels, with dosagelevels being increased until the desired effect is achieved. Thecompounds and compositions of the invention may be administered orallyin an effective amount within the dosage range of about 0.01 to 1000mg/kg in a regimen of single or several divided daily doses. If apharmaceutically acceptable carrier is used in a pharmaceuticalcomposition of the invention, typically, about 5 to 500 mg of a compoundof formulae (I)-(VI) is compounded with a pharmaceutically acceptablecarrier as called for by accepted pharmaceutical practice including, butnot limited to, a physiologically acceptable vehicle, carrier,excipient, binder, preservative, stabilizer, dye, flavor, etc. Theamount of active ingredient in these compositions is such that asuitable dosage in the range indicated is obtained.

[0099] Typical adjuvants which may be incorporated into tablets,capsules and the like include, but are not limited to, binders such asacacia, corn starch or gelatin, and excipients such as microcrystallinecellulose, disintegrating agents like corn starch or alginic acid,lubricants such as magnesium stearate, sweetening agents such as sucroseor lactose, or flavoring agents. When a dosage form is a capsule, inaddition to the above materials it may also contain liquid carriers suchas water, saline, or a fatty oil. Other materials of various types maybe used as coatings or as modifiers of the physical form of the dosageunit. Sterile compositions for injection can be formulated according toconventional pharmaceutical practice. For example, dissolution orsuspension of the active compound in a vehicle such as an oil or asynthetic fatty vehicle like ethyl oleate, or into a liposome may bedesired. Buffers, preservatives, antioxidants and the like can beincorporated according to accepted pharmaceutical practice.

[0100] Pharmacological Assays

[0101] The pharmacological activity of each of the compounds accordingto the invention is determined by the following in vitro assays:

[0102] Inhibition of ADP-Mediated Platelet Aggregation in vitro

[0103] The effect of testing the compound according to the invention onADP-induced human platelet aggregation is preferably assessed in 96-wellmicrotiter assay (see generally the procedures in Jantzen, H. M. et al.(1999) Thromb. Hemost. 81:111-117). Human venous blood is collected fromhealthy, drug-free volunteers into ACD (85 mM sodium citrate, 111 mMglucose, 71.4 mM citric acid) containing PGI₂ (1.25 ml ACD containing1.6 μM PGI₂/10 ml blood; PGI₂ was from Sigma, St. Louis, Mo.).Platelet-rich plasma (PRP) is prepared by centrifugation at 160×g for 20minutes at room temperature. Washed platelets are prepared bycentrifuging PRP for 10 minutes at 730 g and resuspending the plateletpellet in CGS (13 mM sodium citrate, 30 mM glucose, 120 mM NaCl; 2 mlCGS/10 ml original blood volume) containing 1 U/ml apyrase (grade V,Sigma, St. Louis, Mo.). After incubation at 37° C. for 15 minutes, theplatelets are collected by centrifugation at 730 g for 10 minutes andresuspended at a concentration of 3×10⁸ platelets/ml in Hepes-Tyrode'sbuffer (10 mM Hepes, 138 mM NaCl, 5.5 mM glucose, 2.9 mM KCl, 12 mMNaHCO₃, pH 7.4) containing 0.1% bovine serum albumin, 1 mM CaCl₂ and 1mM MgCl₂. This platelet suspension is kept >45 minutes at 37° C. beforeuse in aggregation assays.

[0104] Inhibition of ADP-dependent aggregation is preferably determinedin 96-well flat-bottom microtiter plates using a microtiter plate shakerand plate reader similar to the procedure described by Frantantoni etal., Am. J. Clin. Pathol. 94, 613 (1990). All steps are performed atroom temperature. The total reaction volume of 0.2 ml/well includes inHepes-Tyrodes buffer/0.1% BSA: 4.5×10⁷ apyrase-washed platelets, 0.5mg/ml human fibrinogen (American Diagnostica, Inc., Greenwich, Conn.),serial dilutions of test compounds (buffer for control wells ) in 0.6%DMSO. After about 5 minutes preincubation at room temperature, ADP isadded to a final concentration of 2 μM which induces submaximalaggregation. Buffer is added instead of ADP to one set of control wells(ADP⁻ control). The OD of the samples is then determined at 490 nm usinga microtiter plate reader (Softmax, Molecular Devices, Menlo Park,Calif.) resulting in the 0 minute reading. The plates are then agitatedfor 5 min on a microtiter plate shaker and the 5 minute reading isobtained in the plate reader. Aggregation is calculated from thedecrease of OD at 490 nm at t=5 minutes compared to t=0 minutes and isexpressed as % of the decrease in the ADP control samples aftercorrecting for changes in the unaggregated control samples.

[0105] II. Inhibition of [³H]2-MeS-ADP Binding to Platelets

[0106] Having first determined that the compounds according to theinvention inhibit ADP-dependent platelet aggregation with the aboveassay, a second assay is used to determine whether such inhibition ismediated by interaction with platelet ADP receptors. Utilizing thesecond assay the potency of inhibition of such compounds with respect to[³H]2-MeS-ADP binding to whole platelets is determined. [³H]2-MeS-ADPbinding experiments are routinely performed with outdated humanplatelets collected by standard procedures at hospital blood banks.Apyrase-washed outdated platelets are prepared as follows (all steps atroom temperature, if not indicated otherwise):

[0107] Outdated platelet suspensions are diluted with 1 volume of CGSand platelets pelleted by centrifugation at 1900×g for 45 minutes.Platelet pellets are resuspended at 3-6×10⁹ platelets/ml in CGScontaining 1 U/ml apyrase (grade V, Sigma, St. Louis, Mo.) and incubatedfor 15 minutes at 37° C. After centrifugation at 730×g for 20 minutes,pellets are resuspended in Hepes-Tyrode's buffer containing 0.1% BSA(Sigma, St. Louis, Mo.) at a concentration of 6.66×10⁸ platelets/ml.Binding experiments are performed after >45 minutes resting of theplatelets.

[0108] Alternatively, binding experiments are performed with fresh humanplatelets prepared as described in I. (Inhibition of ADP-MediatedPlatelet Aggregation in vitro), except that platelets are resuspended inHepes-Tyrode's buffer containing 0.1% BSA (Sigma, St. Louis, Mo.) at aconcentration of 6.66×10⁸ platelets/ml. Very similar results areobtained with fresh and outdated platelets.

[0109] A platelet ADP receptor binding assay using the tritiated potentagonist ligand [³H]2-MeS-ADP (Jantzen, H. M. et al. (1999) Thromb.Hemost. 81:111-117) has been adapted to the 96-well microtiter format.In an assay volume of 0.2 ml Hepes-Tyrode's buffer with 0.1% BSA and0.6% DMSO, 1×10⁸ apyrase-washed platelets are preincubated in 96-wellflat bottom microtiter plates for 5 minutes with serial dilutions oftest compounds before addition of 1 nM [³H]2-MeS-ADP([³H]2-methylthioadenosine-5′-diphosphate, ammonium salt; specificactivity 48-49 Ci/mmole, obtained by custom synthesis from Amersham LifeScience, Inc., Arlington Heights, Ill., or NEN Life Science Products,Boston, Mass.). Total binding is determined in the absence of testcompounds. Samples for nonspecific binding may contain 10⁻⁵ M unlabelled2-MeS-ADP (RBI, Natick, Mass.). After incubation for 15 minutes at roomtemperature, unbound radioligand is separated by rapid filtration andtwo washes with cold (4-8° C.) Binding Wash Buffer (10 mM Hepes pH 7.4,138 mM NaCl) using a 96-well cell harvester (Minidisc 96, SkatronInstruments, Sterling, VA) and 8×12 GF/C glassfiber filtermats (PrintedFiltermat A, for 1450 Microbeta, Wallac Inc., Gaithersburg, Md.). Theplatelet-bound radioactivity on the filtermats is determined in ascintillation counter (Microbeta 1450, Wallac Inc., Gaithersburg, Md.).Specific binding is determined by subtraction of non-specific bindingfrom total binding, and specific binding in the presence of testcompounds is expressed as % of specific binding in the absence of testcompounds dilutions.

[0110] It should be understood that the foregoing discussion,embodiments and examples merely present a detailed description ofcertain preferred embodiments. It will be apparent to those of ordinaryskill in the art that various modifications and equivalents can be madewithout departing from the spirit and scope of the invention. All thepatents, journal articles and other documents discussed or cited aboveare herein incorporated by reference.

The claimed invention is:
 1. A compound selected from the groupconsisting of formula (I), formula (II), formula (III), formula (IV),formula (V) and formula (VI):

wherein: A is selected from the group consisting of aryl, substitutedaryl, heteroaryl, substituted heteroaryl, alkylaryl, andalkylheteroaryl; W is selected from the group consisting of aryl,substituted aryl, heteroaryl, and substituted heteroaryl; E is selectedfrom the group consisting of H, —C₁-C₈ alkyl, polyhaloalkyl,—C₃₋₈-cycloalkyl, aryl, alkylaryl, substituted aryl, heteroaryl, andsubstituted heteroaryl; D is selected from the group consisting of—NR¹—(C═O)—R², —O—R¹;

 wherein: R¹ is independently selected from the group consisting of: H,C₁-C₈ alkyl, polyhaloalkyl, —C₃₋₈-cycloalkyl, aryl, alkylaryl,substituted aryl, heteroaryl, substituted heteroaryl, —(C═O)—C₁-C₈alkyl, —(C═O)-aryl, —(C═O)-substituted aryl, —(C═O)-heteroaryl and—(C═O)-substituted heteroaryl; R² is independently selected from thegroup consisting of: aryl, substituted aryl, heteroaryl, and substitutedheteroaryl, or R¹ and R² can be direct linked or can be indirectlylinked through a carbon chain that is from 1 to about 8 carbon atoms inlength, n is an integer from 0-4, m is an integer from 0 or 1, y is aninteger from 0-4 and Q is independently C or N, wherein when Q is a ringcarbon atom, each ring carbon atom is independently substituted by X,wherein X is in each case a member independently selected from the groupconsisting of: hydrogen, halogen, polyhaloalkyl, —OR³, —SR³, —CN, —NO₂,—SO₂R³, —C₁₋₁₀-alkyl, —C₃₋₈-cycloalkyl, aryl, aryl-substituted by 1-4 R³groups, amino, amino-C₁₋₈-alkyl, C₁₋₃-acylamino,C₁₋₃-acylamino-C₁₋₈-alkyl, C₁₋₆-alkylamino, C₁₋₆-alkylamino C₁₋₈ alkyl,C₁₋₆ dialkylamino, C₁₋₆ dialkylamino C₁₋₈ alkyl, C₁₋₆ alkoxy, C₁₋₆alkoxy-C₁₋₆-alkyl, carboxy-C₁₋₆-alkyl, C₁₋₃-alkoxycarbonyl,C₁₋₃-alkoxycarbonyl-C₁₋₆-alkyl, carboxy C₁₋₆ alkyloxy, hydroxy, hydroxyC₁₋₆ alkyl, and a 5 to 10 membered fused or non-fused aromatic ornonaromatic heterocyclic ring system, having 1 to 4 heteroatomsindependently selected from N, O, and S, with the proviso that thecarbon and nitrogen atoms, when present in the heterocyclic ring system,are unsubstituted, mono- or di-substituted independently with 0-2 R⁴groups, wherein R³ and R⁴ are each independently selected from the groupconsisting of: hydrogen, halogen, —CN, —NO₂, —C₁₋₁₀ alkyl,C₃₋₈-cycloalkyl, aryl, amino, amino-C₁₋₈-alkyl, C₁₋₃-acylamino,C₁₋₃-acylamino-C₁₋₈-alkyl, C₁₋₆-alkylamino, C₁₋₆-alkylamino C₁₋₈ alkyl,C₁₆ dialkylamino, C₁₋₆ dialkylamino C₁₋₈ alkyl, C₁₋₆ alkoxy, C₁₋₆alkoxy-C₁₋₆-alkyl, carboxy-C₁₋₆-alkyl, C₁₋₃-alkoxycarbonyl,C₁₋₃-alkoxycarbonyl-C₁₋₆-alkyl, carboxy-C₁₋₆-alkyloxy, hydroxy,hydroxy-C₁₋₆-alkyl, -thio and thio-C₁₋₆-alkyl; Y is selected from thegroup consisting of O, S, N—OR⁵, and NR⁵, wherein R⁵ is selected fromthe group consisting of: H, C₁₋₁₀ alkyl, C₃₋₈-cycloalkyl, and CN; orpharmaceutically acceptable salts and prodrugs.
 2. A compound of claim1, having the following formula:

wherein: R₂ is selected from the group consisting of:

 R₁ is selected from the group consisting of: H, Me and

 W is selected from the group consisting of:

 Y is selected from the group consisting of: O, S, N—C≡N, NH and

and A is selected from the group consisting of:


3. A compound of claim 1, having the following formula,

wherein: n is an integer from 0-4; X is selected from the groupconsisting of: 3-Br, 3-Cl, 4-OMe, H, 3-SO₂Me, 3-N(Me)₂ and3,4,-dimethyl; W is selected from the group consisting of:

 Y is selected from the group consisting of: O, N—C≡N, NH and

 A is selected from the group consisting of:


4. A compound of claim 1, having the following formula:

wherein: Y is selected from the group consisting of: O, N—C≡N, NH and

 A is selected from the group consisting of:


5. A compound of claim 1, having the following formula:

wherein R₁ is selected from the group consisting of: H, Me and

 R₂ is selected from the group consisting of:

 W is selected from the group consisting of:


6. A compound of claim 1, selected from the group consisting of:


7. A pharmaceutical composition for preventing or treating thrombosis ina mammal comprising a therapeutically effective amount of a compoundaccording to claim 1, or a pharmaceutically acceptable salt thereof, anda pharmaceutically acceptable carrier.
 8. A pharmaceutical compositionof claim 7, wherein said therapeutically effective amount is an amounteffective to inhibit platelet aggregation in the mammal.
 9. Apharmaceutical composition of claim 8, wherein said platelet aggregationis platelet ADP-dependent aggregation.
 10. A pharmaceutical compositionof claim 9, wherein said mammal is a human.
 11. A pharmaceuticalcomposition of claim 7, wherein said compound is an effective inhibitorof [³H]2-MeS-ADP binding to platelet ADP receptors.
 12. A pharmaceuticalcomposition for preventing or treating thrombosis in a mammal comprisinga therapeutically effective amount of a compound according to claim 6,or a pharmaceutically acceptable salt thereof, and a pharmaceuticallyacceptable carrier.
 13. A pharmaceutical composition of claim 12,wherein said therapeutically effective amount is an amount effective toinhibit platelet aggregation in the mammal.
 14. A pharmaceuticalcomposition of claim 13, wherein said platelet aggregation is plateletADP-dependent aggregation.
 15. A pharmaceutical composition of claim 14,wherein said mammal is a human.
 16. A pharmaceutical composition ofclaim 12, wherein said compound is an effective inhibitor of[³H]2-MeS-ADP binding to platelet ADP receptors.
 17. A method forpreventing or treating thrombosis in a mammal comprising the step ofadministering to a mammal a therapeutically effective amount of acompound of claim 1 or a pharmaceutically acceptable salt thereof.
 18. Amethod of claim 17, wherein said mammal is a human.
 19. A method ofclaim 17, wherein said mammal is prone to or suffers from acardiovascular disease.
 20. A method of claim 17, wherein saidcardiovascular disease is at least one selected from the groupconsisting of acute myocardial infarction, unstable angina, chronicstable angina, transient ischemic attacks, strokes, peripheral vasculardisease, preeclampsia/eclampsia, deep venous thrombosis, embolism,disseminated intravascular coagulation and thrombotic cytopenic purpura,thrombotic and restenotic complications following invasive proceduresresulting from angioplasty, carotid endarterectomy, post CABG (coronaryartery bypass graft) surgery, vascular graft surgery, stent placementsand insertion of endovascular devices and protheses.